Placenta 60 (2017) 140e144 Contents lists available at ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta Maternal effector T cells within decidua: The adaptive immune response to pregnancy? * D. Lissauer a, M.D. Kilby a, P. Moss b, a Centre for Women's and Newborn's Health and Centre of Endocrinology, Diabetes and Metabolism [CEDAM], College of Medical and Dental Sciences, University of Birmingham and Birmingham Health Partners, UK b Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham and Birmingham Health Partners, UK article info abstract Article history: In human pregnancy the maternal immune system plays a critical role in the regulation of many aspects Received 1 May 2017 of human reproduction including implantation, placentation and defence against infection. Interest has Received in revised form been focussed on the role of uterine natural killer cells (uNK) in the maternal decidua whereas effector 25 August 2017 CD4þ and CD8þ T cells have received much less attention despite the observation that they represent a Accepted 7 September 2017 major proportion of decidual leucocytes in the latter phase of pregnancy. A range of recent studies have demonstrated that human decidual T cells are highly differentiated, express a range of cytokines and Keywords: cytotoxic markers, and demonstrate a unique transcriptional profile characterized by high level Decidua Effector T cell expression of genes involved in interferon-signalling. Moreover, subpopulations of effector T cells fi Interferon demonstrate speci city for fetal tissue and are regulated through expression of inhibitory checkpoint proteins and T regulatory cells. Nevertheless, many questions remain to be answered, such as the po- tential role of maternal effector T cells in either supporting successful pregnancy or potentially clearing fetal cells that have entered the maternal circulation. In addition, there is an increasing interest in the role of maternal effector T cells in the pathogenesis of disorders such as chronic villitis miscarriage, stillbirth, fetal growth restriction and pre-eclampsia. Current debates in relation to these questions will be discussed within this review. © 2017 Published by Elsevier Ltd. 1. Maternal effector T cells comprise the major population of the uterine environment may perhaps be seen to recapitulate short leucocytes within decidua by the end of pregnancy term lymphocyte dynamics over a 9 month period [4]. CD45ROþ effector T cells comprise around 60% of the decidual T cell repertoire The maintenance of a semi-allogeneic fetus within the mother at term whilst representing only 30% of T cells within blood. This represents a considerable challenge to the maternal immune sys- relative increase in ‘antigen-experienced’ T cells could potentially tem during pregnancy [1]. A wide range of mechanisms have been indicate evidence of local activation although it may also reflect postulated as being important and have evolved in order to limit selective recruitment of effector cells into decidual tissue. In this maternal immune recognition of fetal tissue. One of the most regard it is important to compare the phenotypic and functional straightforward approaches might have been to exclude effector features of T cells in the two compartments and this is shown in CD4þ and CD8þ T cells from the decidual bed. However, effector T Table 1. This reveals a number of differences between effector cells cells represent around 60% of the T cell pool in the later stages of in decidua and blood, including the observation that decidual pregnancy [2] and whilst NK cells are relatively more numerous in effector cells are more highly differentiated than peripheral cells, the early stages of pregnancy their numbers remain stable whilst with over 40% of such cells demonstrating a CD27-CD28- pheno- those of T cells show a gradual increase with advancing gestation type compared to less than 20% in blood [5]. [2,3]. As such this temporal replacement of NK cells by T cells This pattern of local activation of decidual T cells might be taken mirrors the kinetics of a peripheral adaptive immune response and to represent recognition of fetal tissue. Fetal trophoblast cells downregulate the expression of HLA-A and HLA-B, and observation that mismatch of polymorphic HLA-C alleles between mother and * Corresponding author. fetus was associated with increased levels of T cell activation pro- E-mail address: [email protected] (P. Moss). vided some of the first support for this hypothesis [6]. https://doi.org/10.1016/j.placenta.2017.09.003 0143-4004/© 2017 Published by Elsevier Ltd. D. Lissauer et al. / Placenta 60 (2017) 140e144 141 Table 1 Comparison of the features of CD45ROþ effector T cells within decidua and maternal peripheral blood at term. Data from Powell et al., (Submitted). Effector T cells within decidua Effector T cells within maternal peripheral blood Percentage of total T cell repertoire ~60% ~30% Degree of differentiation more differentiated less differentiated (~40% CD27-CD28-) (~20% CD27-CD28-) Pattern of cytokine production following stimulation with PMA/ CD4þ: CD4þ: Ionomycin mitogen IFNg, 25%; Il-4, 5% IFNg, 17%; Il-4, 2% CD8þ CD8þ IFNg, 60%; Il-4, 1.2% IFNg, 41%; Il-4, 0.7% Expression of checkpoint proteins CD4þ CD4þ 43% PD-1þ 20% PD-1þ CD8þ CD8þ 68% PD-1þ 25% PD-1þ Frequency of fetal-specific T cells Use of HLA-peptide multimers reveals increased numbers Rare e but potential role in controlling compared to blood fetal chimerism Differentially expressed genes Increase in genes which mediate interferon signalling response 2. The CXCL10-CXCR3 axis is important in attracting effector T following a single male pregnancy and this proportion rose to 50% cells to decidual tissue of those with 2 or more male pregnancies, indicating that allor- eactive cellular immunity is boosted by recurrent episodes of fetal Chemokines are important regulators of leukocyte migration microchimerism. Until recently, it has not been possible to directly and are therefore likely to play a major role in reproductive biology. identify T cells with fetal specificity within decidual tissue but we CXCR3 is a receptor for inflammatory chemokines and studies have also utilized HLA-peptide multimer technology to identify HY- within pregnant mice have shown that it undergoes epigenetic specific CD8 T cells in decidual tissue [5]. Indeed, the frequency of silencing on T cells within decidua [7], although this may be over- such cells is greatly increased compared to peripheral blood and come in the setting of local inflammation [8]. In contrast our indicates that cytotoxic cells with specificity for fetal tissue are findings reveal CXCR3 to be expressed on 17% of human decidual localised in direct anatomical contact. CD4þ T cells, one of many differences found between the immu- nological environment between mice and humans [5]. CXCL10, an important ligand for CXCR3, is strongly expressed and identifies the 4. Effector T cells within decidua display a novel profile of CXCL10-CXCR3 axis as an important mediator of effector cell functional activity migration into decidual tissue. Tilbergs et al studied CD8þ effector T cells within decidual tissue and demonstrated a unique Th1 pattern of high level IFNg 3. Maternal effector T cells within decidua can recognise fetal expression together with low levels of perforin and granzyme [17]. tissue Our own studies of decidual CD4 and CD8þ T cells confirmed IFNg expression in many cells but also revealed expression of IL-4 in a It is now clear that an adaptive immune response against fetal minority population. In particular whilst IFNg expression was tissue develops in most, if not all, human pregnancies. This is observed in 60% of CD8þ T cells, 1.2% of cells also expressed IL-4, a indicated most clearly in the development of alloreactive HLA- value which, whilst relatively modest, was higher than expression specific antibodies and the development of sensitive assays has within 0.7% of CD8þ cells within maternal peripheral blood. revealed that these are found in most mothers following a single Comparable values for CD4þ T cells were 25% and 5% respectively pregnancy [9]. Moreover, the presence of IgG isotypes reveals that and Il-4 expression was markedly higher than on maternal T cells antigen-specific T cell ‘help’ has also been established. The potential from peripheral blood [5]. Interestingly, Il-4 expression can be importance of these antibodies in relation to fetal health is uncer- induced from peripheral T cells following incubation with proges- tain and such responses may simply reflect an epiphenomenon that terone and this ‘Tprog‘ phenotype may therefore partially reflect is of no consequence to pregnancy outcome. However some studies the effect of the local hormonal microenvironment [18,19]. do reveal a weak clinical association and HLA-C specific antibodies We recently completed a comparative transcriptional analysis of have been shown to be more common in women with recurrent effector CD4 and CD8þ T cells from decidua and maternal periph- fetal loss (miscarriage) [10]. eral blood. A wide range of genes were differentially expressed in Given this observation, it is perhaps not surprising that maternal decidual T cells with a striking upregulation of those which encode cellular adaptive immune responses against fetal tissue are also proteins involved in the signalling response to interferon [5]. This generated during human pregnancy. Culture and expansion of profile is highly unusual